mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways
Abstract
Loss of PTEN function leads to activation of phosphoinositide 3-kinase (PI3K) signaling and Akt. Clinical trials are now testing whether mammalian target of rapamycin (mTOR) inhibition is useful in treating PTEN-null cancers. Here, we report that mTOR inhibition induced apoptosis of epithelial cells and the complete reversal of a neoplastic phenotype in the prostate of mice expressing human AKT1 in the ventral prostate. Induction of cell death required the mitochondrial pathway, as prostate-specific coexpression of BCL2 blocked apoptosis. Thus, there is an mTOR-dependent survival signal required downstream of Akt. Bcl2 expression, however, only partially restored intraluminal cell growth in the setting of mTOR inhibition. Expression profiling showed that Hif-1 alpha targets, including genes encoding most glycolytic enzymes, constituted the dominant transcriptional response to AKT activation and mTOR inhibition. These data suggest that the expansion of AKT-driven prostate epithelial cells requires mTOR-dependent survival signaling and activation of HIF-1 alpha, and that clinical resistance to mTOR inhibitors may emerge through BCL2 expression and/or upregulation of HIF-1 alpha activity.
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Several studies have shown that mTOR inhibition decreases HIF-1α and HIF-2α levels under both normoxic and hypoxic conditions.
“Consistent with this, several studies have shown that mTOR inhibition decreases HIF-1α and HIF-2α levels under both normoxic and hypoxic conditions (Hudson et al., 2002;Majumder et al., 2004;Thomas et al., 2006;Mohlin et al., 2015).”
From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Majumder et al., 2004
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- Authors
- Majumder, P. K., Febbo, P. G., Bikoff, R., Berger, R., Xue, Q., McMahon, L. M., Manola, J., Brugarolas, J., McDonnell, T. J., Golub, T. R., Loda, M., Lane, H. A., & Sellers, W. R.
- Affiliations
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- The University of Texas MD Anderson Cancer Center (US)
- Broad Institute (US)
- Novartis (Switzerland) (CH)
- Corresponding author
- Sellers, William R
- ORCID
- Venue
- Nature Medicine
- Published
- 2004-05-23
- Volume
- 10
- Issue
- 6
- Pages
- 594-601
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2164895949
- Cited by
- 964
- References
- 50
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 20 · 2023: 41 · 2022: 16 · 2021: 35 · 2020: 18 · 2019: 29 · 2018: 30 · 2017: 24 · 2016: 41 · 2015: 46 · 2014: 55 · 2013: 51 · 2012: 57
- FWCI
- 24.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA089021, P01 CA 89021)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Keywords
- mTOR inhibition, Akt signaling, prostatic intraepithelial neoplasia, PTEN loss, PI3K signaling, apoptosis, mitochondrial apoptosis, Bcl-2, HIF-1α, glycolytic gene expression, mTOR inhibitor resistance, prostate cancer
- MeSH terms
- Everolimus, Animals, Cell Survival, Epithelial Cells, Humans, Immunosuppressive Agents, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Placebos, Prostate, Prostatic Neoplasms, Protein Kinases, Proto-Oncogene Proteins, Transcription Factors, Signal Transduction, Apoptosis, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins c-bcl-2, Sirolimus, In Situ Nick-End Labeling, Gene Expression Profiling, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, TOR Serine-Threonine Kinases
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